![[Feedback]](/icons/banner/feedbackACT.gif){kind=icon}
![[For Subscribers]](/icons/banner/subscriberACT.gif){kind=icon}
![[Archive]](/icons/banner/archiveACT.gif){kind=icon}
![[Search]](/icons/banner/searchACT.gif){kind=icon}
![[Contents]](/icons/banner/tocACT.gif){kind=icon}
|
|
|
|
|
||
Vol. 28, Issue 6, 655-660, June 2000
Departments of Medicine and Pharmacology, Division of
Clinical Pharmacology, Vanderbilt University School of Medicine,
Nashville, Tennessee
HIV protease inhibitors have proven remarkably effective in
treating HIV-1 infection. However, some tissues such as the brain and
testes (sanctuary sites) are possibly protected from exposure to HIV
protease inhibitors due to drug entry being limited by the membrane
efflux transporter P-glycoprotein, located in the capillary
endothelium. Intravenous administration of the novel and potent
P-glycoprotein inhibitor LY-335979 to mice (1-50 mg/kg) increased
brain and testes concentration of [14C]nelfinavir, up to
37- and 4-fold, respectively, in a dose-dependent fashion. Similar
effects in brain levels were also observed with 14C-labeled
amprenavir, indinavir, and saquinavir. Because
[14C]nelfinavir plasma drug levels were only modestly
increased by LY-335979, the increase in brain/plasma and testes/plasma
ratios of 14- to 17- and 2- to 5-fold, respectively, was due to
increased tissue penetration. Less potent P-glycoprotein inhibitors
like valspodar (PSC-833), cyclosporin A, and ketoconazole, as well as
quinidine and verapamil, had modest or little effect on brain/plasma ratios but increased plasma nelfinavir concentrations due to inhibition of CYP3A-mediated metabolism. Collectively, these findings provide "proof-of-concept" for increasing HIV protease inhibitor
distribution into pharmacologic sanctuary sites by targeted inhibition
of P-glycoprotein using selective and potent agents and suggest a new
therapeutic strategy to reduce HIV-1 viral replication.
This article has been cited by other articles:
|
|
 |
|
  Y. Kitamura, H. Koto, S. Matsuura, T. Kawabata, H. Tsuchiya, H. Kusuhara, H. Tsujimoto, and Y. Sugiyama Modest Effect of Impaired P-glycoprotein on the Plasma Concentrations of Fexofenadine, Quinidine, and Loperamide following Oral Administration in Collies Drug Metab. Dispos., May 1, 2008; 36(5): 807 - 810. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 I. Mahmood and M. D. Green Drug Interaction Studies of Therapeutic Proteins or Monoclonal Antibodies J. Clin. Pharmacol., December 1, 2007; 47(12): 1540 - 1554. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 O. Janneh, E. Jones, B. Chandler, A. Owen, and S. H. Khoo Inhibition of P-glycoprotein and multidrug resistance-associated proteins modulates the intracellular concentration of lopinavir in cultured CD4 T cells and primary human lymphocytes J. Antimicrob. Chemother., November 1, 2007; 60(5): 987 - 993. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Shaik, N. Giri, G. Pan, and W. F. Elmquist P-glycoprotein-Mediated Active Efflux of the Anti-HIV1 Nucleoside Abacavir Limits Cellular Accumulation and Brain Distribution Drug Metab. Dispos., November 1, 2007; 35(11): 2076 - 2085. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Kaddoumi, S.-U. Choi, L. Kinman, D. Whittington, C.-C. Tsai, R. J.Y. Ho, B. D. Anderson, and J. D. Unadkat Inhibition of P-glycoprotein Activity at the Primate Blood-Brain Barrier Increases the Distribution of Nelfinavir into the Brain but Not into the Cerebrospinal Fluid Drug Metab. Dispos., September 1, 2007; 35(9): 1459 - 1462. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Cao, X. Chen, J. Liang, X.-Q. Yu, A.-L. Xu, E. Chan, D. Wei, M. Huang, J.-Y. Wen, X.-Y. Yu, et al. Role of P-glycoprotein in the Intestinal Absorption of Glabridin, an Active Flavonoid from the Root of Glycyrrhiza glabra Drug Metab. Dispos., April 1, 2007; 35(4): 539 - 553. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. D. Unadkat, D. W. Wara, M. D. Hughes, A. A. Mathias, D. T. Holland, M. E. Paul, J. Connor, S. Huang, B.-Y. Nguyen, D. H. Watts, et al. Pharmacokinetics and Safety of Indinavir in Human Immunodeficiency Virus-Infected Pregnant Women Antimicrob. Agents Chemother., February 1, 2007; 51(2): 783 - 786. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. A. Scott, M. Wood, and P. Flood The pronociceptive effect of ondansetron in the setting of p-glycoprotein inhibition. Anesth. Analg., September 1, 2006; 103(3): 742 - 746. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. F. Choo, D. Kurnik, M. Muszkat, T. Ohkubo, S. D. Shay, J. N. Higginbotham, H. Glaeser, R. B. Kim, A. J. J. Wood, and G. R. Wilkinson Differential in Vivo Sensitivity to Inhibition of P-glycoprotein Located in Lymphocytes, Testes, and the Blood-Brain Barrier J. Pharmacol. Exp. Ther., June 1, 2006; 317(3): 1012 - 1018. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. D. Anderson, M. J. May, S. Jordan, L. Song, M. J. Roberts, and M. Leggas DEPENDENCE OF NELFINAVIR BRAIN UPTAKE ON DOSE AND TISSUE CONCENTRATIONS OF THE SELECTIVE P-GLYCOPROTEIN INHIBITOR ZOSUQUIDAR IN RATS Drug Metab. Dispos., April 1, 2006; 34(4): 653 - 659. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. E. Taub, L. Podila, D. Ely, and I. Almeida FUNCTIONAL ASSESSMENT OF MULTIPLE P-GLYCOPROTEIN (P-GP) PROBE SUBSTRATES: INFLUENCE OF CELL LINE AND MODULATOR CONCENTRATION ON P-GP ACTIVITY Drug Metab. Dispos., November 1, 2005; 33(11): 1679 - 1687. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. M. Kalabis, A. Kostaki, M. H. Andrews, S. Petropoulos, W. Gibb, and S. G. Matthews Multidrug Resistance Phosphoglycoprotein (ABCB1) in the Mouse Placenta: Fetal Protection Biol Reprod, October 1, 2005; 73(4): 591 - 597. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Owen, O. Janneh, R. C. Hartkoorn, B. Chandler, P. G. Bray, P. Martin, S. A. Ward, C. A. Hart, S. H. Khoo, and D. J. Back In Vitro Synergy and Enhanced Murine Brain Penetration of Saquinavir Coadministered with Mefloquine J. Pharmacol. Exp. Ther., September 1, 2005; 314(3): 1202 - 1209. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Zhao, K. L. Kunze, and C. A. Lee EVALUATION OF TIME-DEPENDENT INACTIVATION OF CYP3A IN CRYOPRESERVED HUMAN HEPATOCYTES Drug Metab. Dispos., June 1, 2005; 33(6): 853 - 861. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. E. Edwards, J. Alcorn, J. Savolainen, B. D. Anderson, and P. J. McNamara Role of P-Glycoprotein in Distribution of Nelfinavir across the Blood-Mammary Tissue Barrier and Blood-Brain Barrier Antimicrob. Agents Chemother., April 1, 2005; 49(4): 1626 - 1628. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Kim, J. A. Johnson, and H. Derendorf Differences in Drug Pharmacokinetics Between East Asians and Caucasians and the Role of Genetic Polymorphisms J. Clin. Pharmacol., October 1, 2004; 44(10): 1083 - 1105. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. U. C. Sankatsing, J. H. Beijnen, A. H. Schinkel, J. M. A. Lange, and J. M. Prins P Glycoprotein in Human Immunodeficiency Virus Type 1 Infection and Therapy Antimicrob. Agents Chemother., April 1, 2004; 48(4): 1073 - 1081. [Full Text] [PDF]
|
|
|
|
|
|
C. Anthonypillai, R. N. Sanderson, J. E. Gibbs, and S. A. Thomas The Distribution of the HIV Protease Inhibitor, Ritonavir, to the Brain, Cerebrospinal Fluid, and Choroid Plexuses of the Guinea Pig J. Pharmacol. Exp. Ther., March 1, 2004; 308(3): 912 - 920. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. Mizuno, T. Niwa, Y. Yotsumoto, and Y. Sugiyama Impact of Drug Transporter Studies on Drug Discovery and Development Pharmacol. Rev., September 1, 2003; 55(3): 425 - 461. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. W. Haas, B. Johnson, J. Nicotera, V. L. Bailey, V. L. Harris, F. B. Bowles, S. Raffanti, J. Schranz, T. S. Finn, A. J. Saah, et al. Effects of Ritonavir on Indinavir Pharmacokinetics in Cerebrospinal Fluid and Plasma Antimicrob. Agents Chemother., July 1, 2003; 47(7): 2131 - 2137. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W E Evans Pharmacogenomics: marshalling the human genome to individualise drug therapy Gut, May 1, 2003; 52(90002): ii10 - 18. [Abstract] [Full Text]
|
|
|
|
 |
|
 A. Siddiqui, R. Kerb, M. E. Weale, U. Brinkmann, A. Smith, D. B. Goldstein, N. W. Wood, and S. M. Sisodiya Association of Multidrug Resistance in Epilepsy with a Polymorphism in the Drug-Transporter Gene ABCB1 N. Engl. J. Med., April 10, 2003; 348(15): 1442 - 1448. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. Imbert, M. Jardin, C. Fernandez, J. C. Gantier, F. Dromer, G. Baron, F. Mentre, L. van Beijsterveldt, E. Singlas, and F. Gimenez Effect of Efflux Inhibition on Brain Uptake of Itraconazole in Mice Infected with Cryptococcus neoformans Drug Metab. Dispos., March 1, 2003; 31(3): 319 - 325. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. E. Evans and H. L. McLeod Pharmacogenomics -- Drug Disposition, Drug Targets, and Side Effects N. Engl. J. Med., February 6, 2003; 348(6): 538 - 549. [Full Text] [PDF]
|
|
|
|
|
|
M. T. Huisman, J. W. Smit, H. R. Wiltshire, J. H. Beijnen, and A. H. Schinkel Assessing Safety and Efficacy of Directed P-Glycoprotein Inhibition to Improve the Pharmacokinetic Properties of Saquinavir Coadministered with Ritonavir J. Pharmacol. Exp. Ther., February 1, 2003; 304(2): 596 - 602. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. G. Solon, S. K. Balani, G. Luo, T. J. Yang, P. J. Haines, L. Wang, T. Demond, S. Diamond, D. D. Christ, L.-S. Gan, et al. Interaction of Ritonavir on Tissue Distribution of a [14C]L-Valinamide, a Potent Human Immunodeficiency Virus-1 Protease Inhibitor, in Rats Using Quantitative Whole-Body Autoradiography Drug Metab. Dispos., November 1, 2002; 30(11): 1164 - 1169. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. H. Khoo, P. G. Hoggard, I. Williams, E. R. Meaden, P. Newton, E. G. Wilkins, A. Smith, J. F. Tjia, J. Lloyd, K. Jones, et al. Intracellular Accumulation of Human Immunodeficiency Virus Protease Inhibitors Antimicrob. Agents Chemother., October 1, 2002; 46(10): 3228 - 3235. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. F.S. Kehrer, R. H.J. Mathijssen, J. Verweij, P. de Bruijn, and A. Sparreboom Modulation of Irinotecan Metabolism by Ketoconazole J. Clin. Oncol., July 15, 2002; 20(14): 3122 - 3129. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. M. Brady, N. J. Cherrington, D. P. Hartley, S. C. Buist, N. Li, and C. D. Klaassen Tissue Distribution and Chemical Induction of Multiple Drug Resistance Genes in Rats Drug Metab. Dispos., July 1, 2002; 30(7): 838 - 844. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. E. Edwards, K. R. Brouwer, and P. J. McNamara GF120918, a P-Glycoprotein Modulator, Increases the Concentration of Unbound Amprenavir in the Central Nervous System in Rats Antimicrob. Agents Chemother., July 1, 2002; 46(7): 2284 - 2286. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Savolainen, J. E. Edwards, M. E. Morgan, P. J. McNamara, and B. D. Anderson Effects of a P-Glycoprotein Inhibitor on Brain and Plasma Concentrations of Anti-Human Immunodeficiency Virus Drugs Administered in Combination in Rats Drug Metab. Dispos., May 1, 2002; 30(5): 479 - 482. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Merino, A. I. Alvarez, J. G. Prieto, and R. B. Kim The Anthelminthic Agent Albendazole Does Not Interact with P-Glycoprotein Drug Metab. Dispos., April 1, 2002; 30(4): 365 - 369. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Lee, L. Schlichter, M. Bendayan, and R. Bendayan Functional Expression of P-glycoprotein in Rat Brain Microglia J. Pharmacol. Exp. Ther., October 1, 2001; 299(1): 204 - 212. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. V. Batrakova, D. W. Miller, S. Li, V. Y. Alakhov, A. V. Kabanov, and W. F. Elmquist Pluronic P85 Enhances the Delivery of Digoxin to the Brain: In Vitro and in Vivo Studies J. Pharmacol. Exp. Ther., April 13, 2001; 296(2): 551 - 557. [Abstract] [Full Text]
|
|
|
|
 |
|
 M. T. Huisman, J. W. Smit, H. R. Wiltshire, R. M. W. Hoetelmans, Jos. H. Beijnen, and A. H. Schinkel P-Glycoprotein Limits Oral Availability, Brain, and Fetal Penetration of Saquinavir Even with High Doses of Ritonavir Mol. Pharmacol., April 1, 2001; 59(4): 806 - 813. [Abstract] [Full Text]
|
|
 |
 |
 |
|
 |
 |
 |
